MTOR: Uncovering the link from nutrients to growth
The mechanisms that regulate organismal growth and coordinate it with the availability of nutrients were unknown until a few decades ago. We now know that one pathway—the mechanistic target of rapamycin (mTOR) pathway—is the major nutrient-sensitive regulator of growth in animals and plays a central role in physiology, metabolism, the aging process, and common diseases. This work describes the development of the mTOR field, from its origins in studies into the mechanism of action of the drug rapamycin to our increasingly sophisticated understanding of how nutrients are sensed.
In my PNAS Inaugural Article, I describe the development of the mTOR field, starting with efforts to understand the mechanism of action of the drug rapamycin, which ∼25 y ago led to the discovery of the mTOR protein kinase. I focus on insights that we have contributed and on work that has been particularly influential to me, as well as provide some personal reflections and stories. We now appreciate that, as part of two distinct complexes, mTORC1 and mTORC2, mTOR is the major regulator of growth (mass accumulation) in animals and is the key link between the availability of nutrients in the environment and the control of most anabolic and catabolic processes. Nutrients signal to mTORC1 through the lysosome-associated Rag GTPases and their many regulators and associated cytosolic and lysosomal nutrient sensors. mTOR signaling is deregulated in common diseases, like cancer and epilepsy, and mTORC1 is a well-validated modulator of aging in multiple model organisms. There is significant excitement around using mTORC1 inhibitors to treat cancer and neurological disease and, potentially, to improve healthspan and lifespan.
I decided to use my PNAS Inaugural Article to write about the development of the mTOR field and to provide some personal recollections that highlight work that has been particularly influential to me. I suppose one writes such pieces when one has been around for a while. This appears to be the case, even though I am still surprised when someone refers to me as senior or I am asked by young scientists to talk about my career.
In the fall of 1992, I went to see Sol Snyder about a thesis project. I remember the meeting well, as I would meet with Sol one-on-one very few times during my time in his laboratory. Sol sat in a comfy office chair in the balled-up way that those of us in his laboratory found impossible to mimic, and he was quiet, knowing the power of silence (we assumed it was a trick he learned during his psychiatry training). I was nervous and blurted out that I wanted to talk about potential projects. After a bit, he said, “Well, David, we work on the brain.” That seemed like a great start, as I wanted to do neuroscience, but then more silence followed, and, as I was to learn, that meant the conversation was over. I left unsettled because the brain was obviously a big topic, meaning I was project-less. That conversation though was likely the most important scientific interaction of my career, as Sol was giving me the freedom to do whatever I wanted, which allowed me to develop my own research direction at a relatively young age. I never did end up working on the brain, but I do take some comfort in having originally purified mTOR from brains.